Continuous Positive Airway Pressure (CPAP) for severe pneumonia in low- and middle-income countries: A systematic review of contextual factors

Background Continuous positive airway pressure (CPAP) may have a role in reducing the high mortality in children less than 5 years with World Health Organization (WHO) severe pneumonia. More evidence is needed to understand important contextual factors that impact on implementation, effectiveness, and safety in low resource settings. Methods We conducted a systematic review of Medline, Embase and Pubmed (January 2000 to August 2020) with terms of “pneumonia”, “CPAP” and “child”. We included studies that provided original clinical or non-clinical data on the use of CPAP in children (28 days-4 years) with pneumonia in low- or middle-income countries. We used standardised tools to assess study quality, and grade levels of evidence for clinical conclusions. Results are presented as a narrative synthesis describing context, intervention, and population alongside outcome data. Results Of 902 identified unique references, 23 articles met inclusion criteria, including 6 randomised controlled trials, one cluster cross over trial, 12 observational studies, 3 case reports and 1 cost-effectiveness analysis. There was significant heterogeneity in patient population, with wide range in mortality among participants in different studies (0%-55%). Reporting of contextual factors, including staffing, costs, and details of supportive care was patchy and non-standardised. Current evidence suggests that CPAP has a role in the management of infants with bronchiolitis and as escalation therapy for children with pneumonia failing standard-flow oxygen therapy. However, CPAP must be implemented with appropriate staffing (including doctor oversight), intensive monitoring and supportive care, and technician and infrastructure capacity. We provide practical guidance and recommendations based on available evidence and published expert opinion, for the adoption of CPAP into routine care in low resource settings and for reporting of future CPAP studies. Conclusions CPAP is a safe intervention in settings that can provide intensive monitoring and supportive care, and the strongest evidence for a benefit of CPAP is in infants (aged less than 1 year) with bronchiolitis. The available published evidence and clinical experience can be used to help facilities assess appropriateness of implementing CPAP, guide health workers in refining selection of patients most likely to benefit from it, and provide a framework for components of safe and effective CPAP therapy. Protocol registration PROSPERO registration: CRD42020210597.

Appendix S1 -Further details of study methods including search strategy, data extraction and data management PICOTS • Population -Children aged 28 days-5 years with pneumonia defined according to WHO criteria.
• Intervention -CPAP (any form) • Comparison -usual care, low-flow, or high flow oxygen • Outcomes addressed -acceptability, feasibility, safety (unintended effects, practice points, required capacity) and / or efficacy (change in clinical signs, rates of treatment failure, length of stay, and mortality) • Time period -2000 to present • Setting -hospitals (secondary and tertiary) in low and middle income countries (as defined by the World Bank) • Study types -All relevant published randomised controlled trials and observational studies, including case series and cohort studies, and relevant meta-analyses.

Information sources
Literature search strategies were developed using medical subject headings (MeSH) and text words related to CPAP, pneumonia and lower respiratory tract infection, and children. We searched MEDLINE (OVID interface), EMBASE (OVID interface) and PubMed for all relevant published papers.
We scanned the reference lists of included studies or relevant reviews identified through the search.
Where appropriate, authors were contacted to get more information on the contexts in which their studies took place.

Search strategy
Both qualitative and quantitative studies were sought. No study design, date or language limits were imposed on the search. Medline, EMBASE, and PubMed were searched from inception. The specific search strategies were created by a Health Sciences Librarian with expertise in systematic review searching. The MEDLINE strategy was developed with input from the project team. The draft MEDLINE search strategy is included below. This was then adapted to the syntax and subject headings of the other databases.

Data management
All search results were saved in a shared file accessible to all members of the study team, and citations saved in EndNote. When reviewing papers for inclusion and exclusion records accessible to all team members were kept in the shared folder and on password protected computers.

Selection process
The titles and abstracts of all papers identified though the search were reviewed by two independent reviewers for inclusion or exclusion according to the above criteria. We obtained full reports for all titles that appeared to meet the inclusion criteria or where there was any uncertainty.
Two independent reviewers screened the full text reports and decided whether these meet the inclusion criteria. We sought additional information from study authors where necessary to resolve questions about eligibility. We resolved disagreements through discussion with the team. We recorded the reasons for excluding trials. Neither of the review authors were blind to the journal titles or to the study authors or institutions.

Data collection process
We used a standardised form of specific items (see below) with which 2 independent reviewers extracted data from each eligible study and entered in to an Excel spreadsheet. Reviewers resolved disagreements by discussion, and any unresolved disagreements were discussed with the whole team. We contacted study authors to resolve any uncertainties.

Data Items
For all papers included in the study we sought the following information regarding potential variables and context in which the study took place. We documented whether this data was available in the published papers or whether it was acquired from contact with the authors or other means. If we were unable to find this data this was also noted. Secondary outcomes that we reviewed were: -Length of Stay -Change in clinical signs -Respiratory rate -Oxygen saturations -Heart rate -Treatment failure rates -Rates of children needing intubation -Other issues raised regarding -acceptability -feasibility -unintended effects -practice points -required capacity

Quality Assessment and Risk of Bias in individual studies
Included studies may or may not have a comparison group. To assess the quality of and risk of bias within included studies, the methodological quality of potential studies was assessed by using the Effective Public Healthcare Panacea Project (EPHPP) QA Tool. Using this tool, studies were rated as strong, moderate or weak with respect to selection bias, study design, confounders, blinding, data collection method, withdrawals and dropouts, and a global rating. This was undertaken by two separate reviewers. Where there was disagreement, a third reviewer was used as an arbitrator.